The small molecule drug diminazene aceturate inhibits liver injury and biliary fibrosis in mice

• Published in: Scientific reports 2018-07, Vol.8 (1), p.10175-14, Article 10175
• Main Authors: Rajapaksha, Indu G., Mak, Kai Y., Huang, Ping, Burrell, Louise M., Angus, Peter W., Herath, Chandana B.
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/21; 38; 38/77; 64; 64/60; 692/4020/4021/1328/1325; 692/4020/4021/1607/1605; 82; 82/51; 82/80; ACE2; Angiotensin; Angiotensin-Converting Enzyme 2; Animal models; Animals; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP-Binding Cassette Sub-Family B Member 4; Bile; Bile ducts; Cell Line; Cell lines; Cytokines - metabolism; Diminazene - analogs & derivatives; Diminazene - pharmacology; Diminazene - therapeutic use; Drug resistance; Enzymes; Fibrosis; Hepatic Stellate Cells; Humanities and Social Sciences; Humans; Inflammation; Kupffer Cells; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Cirrhosis, Experimental - drug therapy; Liver Cirrhosis, Experimental - etiology; Liver Cirrhosis, Experimental - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Multidrug resistance; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - metabolism; Overexpression; Peptidyl-Dipeptidase A - metabolism; Reactive Oxygen Species - metabolism; Renin; Renin-Angiotensin System - drug effects; Science; Science (multidisciplinary); Smad2 protein; Stellate cells; Transcription activation; Transcription factors; Treatment Outcome; Trypanosomiasis; Vector-borne diseases
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-28490-y

There is no established medical therapy to treat biliary fibrosis resulting from chronic inflammation in the biliary tree. We have recently shown that liver-specific over-expression of angiotensin converting enzyme 2 (ACE2) of the renin angiotensin system (RAS) ameliorated liver fibrosis in mice. Diminazene aceturate (DIZE), a small molecule drug approved by the US Food and Drug Administration, which is used to treat human trypanosomiasis, has been shown to have antifibrotic properties by enhancing ACE2 activity. In this study we sought to determine the therapeutic potential of DIZE in biliary fibrosis using bile duct ligated and multiple drug resistant gene-2 knockout mice. Additionally, human hepatic stellate (LX-2) and mouse Kupffer (KUP5) cell lines were used to delineate intracellular pathways. DIZE treatment, both in vivo and in vitro , markedly inhibited the activation of fibroblastic stellate cells which was associated with a reduced activation of Kupffer cells. Moreover, DIZE-inhibited NOX enzyme assembly and ROS generation, activation of profibrotic transcription factors including p38, Erk1/2 and Smad2/3 proteins and proinflammatory and profibrotic cytokine release. These changes led to a major reduction in biliary fibrosis in both models without affecting liver ACE2 activity. We conclude that DIZE has a potential to treat biliary fibrosis.